Novel Synthetic Cannabinoid AB‐PINACA Produces THC‐Like Behavioral and Cellular Effects Through activation of the Cannabinoid CB1 Receptor

Abstract

Novel synthetic cannabinoid AB‐PINACA has been identified in herbal products marketed as K2/Spice. Limited information exists on the affinity, intrinsic efficacy, or acute and repeated in vivo effects elicited by AB‐PINACA. In in vitro receptor binding studies, AB‐PINACA displayed high affinity at the CB1R where it functioned as a full agonist. In the tetrad assay, mice injected with 3 mg/kg AB‐PINACA exhibited hypothermia, antinociception, catalepsy, and hypolocomotion, all of which are classical cannabinoid agonist effects. Importantly, these effects were attenuated by rimonabant, a CB1R antagonist/inverse agonist, suggesting that AB‐PINACA mediates these behavioral effects through activation of the CB1R. Mice previously prepared with radiotelemetry probes capable of simultaneously monitoring core body temperature and locomotor activity were repeatedly administered 3 mg/kg AB‐PINACA once every 24 hrs for 5‐days. Mice repeatedly administered AB‐PINACA developed rapid and progressive tolerance to hypothermic effects, and this tolerance was still evident when re‐challenged with the same dose after a 14‐day drug abstinence period. However, no tolerance developed to hypolocomotion. Lastly, mice were administered 30 mg/kg THC repeatedly for 4 days. We have previously shown that this dose regimen produces downregulation and desensitization of CB1Rs and elicits tolerance to cannabinoid induced hypothermia. On Day 5 these mice were challenged with 3 mg/kg AB‐PINACA to determine cross‐tolerance. These data demonstrate that – similar to other high‐efficacy synthetic cannabinoid drugs of abuse – the intrinsic efficacy, acute and repeated in vivo effects of AB‐PINACA are similar to those of THC, and are mediated through agonist interactions with CB1Rs.Support or Funding InformationThis work was supported by RR029884, RR020146 and UAMS Department of Pharmacology and Toxicology.